Like most neurodegenerative disorders, Parkinson's disease (PD) has as its pathological hallmark specific degeneration of certain neuronal subtypes. Specifically, dopamine neurons in the substantia nigra (SN) are exquisitely sensitive to damage in human PD and in animal models of PD, such as administration of the mitochondrial complex I poison rotenone (a common pesticide) to rats. This is in contrast to the relative resistance of other types of neurons. The molecular underpinnings for this selective neuronal vulnerability are unknown. Since inhibition of mitochondrial metabolism by rotenone recapitulates behavioral signs and neuropathological findings of PD, we hypothesize that differences in energy metabolism between susceptible and resistant neurons might underlie differential vulnerability. In the current proposal, we will: (1) evaluate the metabolic transcriptional response to complex I inhibition; (2) test the acute regulation of energy metabolism in dopamine neurons; and (3) determine if modulation of energy metabolism is protective in an in vitro model of PD. These experiments will provide a detailed understanding of mitochondrial energy metabolism in dopamine neurons and give insight into the pathogenesis and potential treatment of PD. The research outlined above is part of a customized five-year plan of training and career development for the Principal Investigator. The proposal includes active mentoring by experienced scientists, access to diverse resources, and an environment uniquely suited to help the PI develop as an independent physician scientist.